Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects.
Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects.
复制标题
DOI：
10.3389/fchem.2022.889737
复制
发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
具有膦酸酯基团的化合物，即通过 P-C 键直接连接到分子上的 –P(O)(OH)2 基团，可在各种生物医学应用中作为合适的不可水解磷酸盐模拟物。原则上，它们经常抑制利用各种磷酸盐作为底物的酶。在这篇综述中，我们主要关注源自我们研究所（布拉格有机化学与生物化学研究所）的生物活性膦酸盐；即，无环核苷膦酸酯（ANP，例如阿德福韦、替诺福韦和西多福韦）和非核苷膦酸酯的衍生物，例如2-（膦酰基甲基）戊二酸（2-PMPA）。报道了它们的前药合成和修饰的主要策略。除了临床上使用的 ANP 抗病毒药物外，还特别关注新出现的感染和许多病原体对标准治疗产生的耐药性的新生物活性分子。这些新结构包括2,4-二氨基-6-[2-(膦酰甲氧基)乙氧基]嘧啶或所谓的“开环”衍生物、以5-氮杂胞嘧啶作为碱基部分的无环核苷膦酸酯、侧链氟化ANP、氮杂/脱氮嘌呤ANP。当通过衍生其带电功能而转化为适当的前药时，所有这些化合物都显示出成为治疗病毒感染的候选药物的巨大潜力。具有合适药代动力学的ANP前药包括氨基酸氨基磷酸酯、新戊酰氧基甲基(POM)和异丙氧基羰氧基甲基(POC)酯、烷基和烷氧基烷基酯、水杨酸酯、(甲基-2-氧代-1，3-二氧杂环戊醇-4-基)甲基(ODOL)酯和拟肽前药。我们还重点关注与 9-[2-(膦酰甲氧基)乙基]鸟嘌呤及其前药相关的细胞抑制剂的故事，这些药物最终导致了兽药雷巴克沙丁的开发。目前还研究了各种新的 ANP 结构作为抗寄生虫药，特别是抗疟药，例如具有 2-(膦酰基乙氧基)乙基部分的鸟嘌呤和次黄嘌呤衍生物、它们的硫杂类似物和 N-支化衍生物。除了 ANP 及其类似物之外，我们还描述了 2-(膦酰甲基)戊二酸 (2-PMPA) 的前药，它是谷氨酸羧肽酶 II (GCPII) 的有效抑制剂，也称为前列腺特异性膜抗原 (PSMA)。谷氨酸羧肽酶 II 抑制剂（包括 2-PMPA）已被发现对由谷氨酸兴奋性毒性引起的神经系统疾病的各种临床前模型有效。不幸的是，它的高极性特性和由此导致的低生物利用度严重限制了其临床应用的潜力。为了克服这个问题，已经使用各种前药策略来用新戊酰氧基甲基、POC、ODOL和烷基酯来掩蔽羧酸酯和/或膦酸酯官能团。化学和生物学特性鉴定出口服生物利用度高出 44-80 倍的前药 (tetra-ODOL-2-PMPA)。
Compounds with a phosphonate group, i.e., –P(O)(OH)2 group attached directly to the molecule via a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called “open-ring” derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44–80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).
登录
查看更多内容
影响因子：
3.4
作者：
Brehova, Petra;Smidkova, Marketa;Skacel, Jan;Dracinsky, Martin;Mertlikova-Kaiserova, Helena;Velasquez, Monica P. Soto;Watts, Val J.;Janeba, Zlatko
通讯作者：
Janeba, Zlatko
影响因子：
3.4
作者：
Česnek M;Šafránek M;Dračínský M;Tloušťová E;Mertlíková-Kaiserová H;Hayes MP;Watts VJ;Janeba Z
通讯作者：
Janeba Z
影响因子：
--
作者：
Arimilli, MN;Kim, CU;Bischofberger, N
通讯作者：
Bischofberger, N
影响因子：
4.9
作者：
Birkus, Gabriel;Bam, Rujuta A.;Cihlar, Tomas
通讯作者：
Cihlar, Tomas
影响因子：
7.6
作者：
Valiaeva, Nadejda;Prichard, Mark N.;Buller, R. Mark;Beadle, James R.;Hartline, Caroll B.;Keith, Kathy A.;Schriewer, Jill;Trahan, Julissa;Hostetler, Karl Y.
通讯作者：
Hostetler, Karl Y.